This application is generally in the field of polymeric materials for use in medicine, and more particularly relates to polyalkylene glycol-hyaluronic acid formulations. Throughout this application, various publications are referenced. The disclosures of those publications are hereby incorporated by reference into this application in their entireties.
Tailored biocompatible materials are widely used in medicine. These materials may be used to seal tissue after surgery, coat tissue to prevent adhesions, adhere tissue to tissue, stimulate regeneration of cartilage, bone and other tissue, and provide local bulking or a substrate for cell growth through implantation into sites in the body. These materials may also be used to deliver drugs, locally or systemically, to deliver cells to particular sites in the body, or to protect cells from attack by the immune system.
An important class of materials useful in for these types of applications is the polysaccharide, hyaluronic acid (HA), and its salts and derivatives. HA is found in the body serving in a variety of functions. The tissue adherence of unmodified HA is not strong. HA can be formed into a gel in the presence of trivalent ions and can be cross-linked to form gels of varying viscosity.
Reactive macromers, particularly of polyethylene glycol (PEG) and related polyalkylene glycols (PAGs), can be used to form gels. These gels also have some drawbacks. For instance, PAGs require a minimum concentration to form gels, typically several percent but preferably higher. The PAGs also have a tendency to swell after polymerization. They are often highly water-soluble. It is frequently difficult to achieve a sufficiently high viscosity in PAG solutions that the solution stays in place during polymerization. PAG solutions also typically have relatively small pores, which do not facilitate cell entry in tissue engineering applications.
Therefore PAGs have been mixed with other polymers to form a solution with the necessary properties to form the desired gels. Many water-soluble polymers are incompatible with PAGs and separate to form two or more phases in aqueous solutions. The best known of these phase-separating pairs are mixtures of PEG with dextran and with other polymers. Only a few polymers are known to interact, in the absence of specific group interactions (as distinguished from nonspecific bonding by hydrogen bonds and the like) or having opposite charges. These include PEG and polyacrylic acid, but the complex is reportedly formed only at low pH (e.g. pH 3–4) where some of the acrylate carboxyls are protonated. Thus, on mixing polymers it is expected that either no interaction or phase separation will occur.
HA and certain other polymers, herein referred to as “PAG-interacting polymers” (“PIPs”), exhibit an interaction with PAGs and PAG-based reactive macromers, producing a solution with a very high viscosity when mixed together. This result is described in U.S. Pat. No. 4,629,623 to Balazs et al. U.S. Pat. No. 4,629,623 discloses that high molecular weight hyaluronic salts and water soluble poly(ethylene oxides) form viscoelastic compositions which can be used in cosmetic formulations.
U.S. Pat. Nos. 6,017,301, 6,034,140, and 6,133,325 to Schwartz et al. teach forming bioadhesive, bioresorbable, anti-adhesion compositions from carboxyl-containing polysaccharides, such as carboxymethylcellulose (CMC), and polyethers, such as polyethyleneoxide (PEO). Schwartz teaches that compositions with the desired properties can be formed at a pH between 3 and 5 due to an association complex forming between the carboxyl containing polysaccharide and the polyether. The compositions are either dried and then applied to the body, or applied to the body in the liquid form.
It is therefore an object of the present invention to provide polymeric mixtures with an increased viscosity.
It is a further object of the present invention to provide methods for administering to a site in a patient a liquid which forms a bioadhesive, flexible gel at the site of administration.
It is a further object of the invention to deliver bioactive compounds to a patient through the application of viscous solutions which form gels.